cGAS signaling in oxidative retinal damage

Ohio State University, Columbus OH

Investigators

Abstract

SUMMARY Oxidative stress is a principal driver in the development and progression of various debilitating ocular diseases including the age-related macular degeneration (AMD). Because of its intense exposure to light combined with its high oxygen consumption and the presence of its photosensitizing endogenous chromophores, retinal tissue is uniquely susceptible to oxidative stress. Recent findings, both from our research and others, have unveiled that oxidative stress—a crucial pathogenic factor in AMD—triggers the release of nuclear and mitochondrial DNA (self-DNA) into the cytosol, culminating in the activation of cellular innate immune pathway called cGAS-STING. Remarkably, our preliminary data indicate that this pathway is activated not only in acute but also in chronic mouse models of oxidative retinal damage. This conserved response positions cGAS-STING pathway as a promising therapeutic target for halting the characteristic slow and progressive deterioration of retinal structure and function in AMD. Therefore, a comprehensive understanding of the mechanism by which self-DNA translocates to the cytosol, as well as the details of the cGAS-STING-initiated effector mechanisms activated during oxidative retinal damage is critical. To bridge this knowledge gap, we propose a multifaceted investigation utilizing both chronic and acute mouse models of oxidative retinal degeneration. In Aim 1, we will investigate the molecular mechanisms governing the escape of self-DNA into cytosolic compartment. Aim 2 will focus on defining the activation of the full range of cGAS-driven effector pathways in mouse retinal and RPE tissue enduring acute and chronic oxidative stress. Aim 3 will evaluate the potential protective benefits of inhibiting cGAS signaling in chronic RPE degeneration in Sod2fox/floxVMD2-Cre mouse model as well define how cGAS- STING signaling modulates gene expression and function in specific retinal cell types employing single cell RNAseq analysis. Collectively, our proposed studies aim to reveal intricate mechanisms of cGAS-STING involvement in AMD-related RPE and retinal deterioration hence hold significant promise for the development of innovative therapeutic strategies